F. M. Singer et al., "New Inhibitors of in vitro Conversion of Acetate and Mevalonate to Cholesterol", Proc. Soc. Exper. Biol. Med., 102, 370 (1959) and F. H. Hulcher, "Inhibition of Hepatic Cholesterol Biosynthesis by 3,5-Dihydroxy -3,4,4,-trimethylvaleric Acid and its Site of Action," Arch. Biochem. Biophys., 146, 422 (1971) disclose that certain mevalonate derivatives inhibit the biosynthesis of cholesterol.
Singer et al. reported that fluoromevalonic acid is more effective in inhibiting biosynthesis of cholesterol (as measured by in vitro conversion of labeled acetate and labeled mevalonate into cholesterol) than .DELTA.4-androstene-17.alpha.-ol-3-one -17.beta.-oic acid and .DELTA.l-testololactone.
Hulcher reported that an analog of mevalonic acid, namely, 3,5-dihydroxy-3,4,4-trimethylvaleric acid strongly inhibits cholesterol biosynthesis by rat liver homogenates.
U.S. Pat. No. 3,983,140 to Endo et al. discloses the fermentation product ML-236B referred to generically as compactin ##STR3## (also referred to as mevastatin) which is prepared by cultivation of a microorganism of the genus Penicillium. This fermentation process is disclosed in U.S. Pat. No. 4,049,495 issued Sept. 20, 1977 to Endo et al.
Brown, A. G., et al., (Beecham Pharmaceuticals Research Div.), "Crystal and Molecular Structure of Compactin, a New Antifungal Metabolite from Penicillium Brevicompactum", J. Chem. Soc. Perkin I. 1165-1170 (1976) confirms that compactin has a complex mevalonolactone structure as disclosed by Endo et al. in the above patents.
U.S. Pat. No. 4,231,938 to Monaghan et al. discloses mevinolin (lovastatin, Monacolin K) ##STR4## (also referred to as MK-803) which is prepared by culturing a microorganism of the genus Aspergillus.
U.S. Pat. No. 4,346,227 to Terahara et al discloses pravastatin ##STR5##
Pravastatin is prepared by the enzymatic hydroxylation of compactin or its carboxylic acid as disclosed in U.S. Pat. No. 4,410,629 to Terahara et al.
U.S. Pat. No. 4,448,979 issued May 15, 1984 to Terahara et al discloses the lactone of pravastatin.
U.S. Pat. Nos. 4,444,784 and 4,450,171 to Hoffman et al disclose various antihypercholesterolemic compounds including synvinolin (simvastatin) ##STR6## as well as compounds of the structures ##STR7## wherein R.sup.1 is H or CH.sub.3, R can be an alkyl group including ##STR8## X, Y and Z are single and/or double bonds in all possible combinations.
European Patent Application 0065835A1 filed by Sankyo discloses cholesterol biosynthesis inhibiting compounds of the structure ##STR9## and their corresponding free carboyxlic acids, which may be represented by the following formula ##STR10## (in which one of R.sup.1 and R.sup.2 represents a hydrogen atom and the other represents a hydroxy group), and salts and esters of the carboxylic acids.
European Patent Application 0142146A2 filed by Merck discloses mevinolin-like compounds of the structure ##STR11## wherein
R.sup.1 is
1) hydrogen, PA1 2) C.sub.1-4 alkyl, PA1 3) 2,3-dihydroxypropyl, PA1 4) alkali metal cation, such as Na.sup.+, or K.sup.+, or PA1 5) ammonium of formula NR.sup.3 R.sup.4 R.sup.5 R.sup.6 wherein R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are independently hydrogen or C.sub.1-4 alkyl or two of R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are joined together to form a 5 or 6-membered heterocycle such as pyrrolidino or piperidino with the nitrogen to which they are attached; PA1 a) hydrogen, PA1 b) halogen, such as bromo, chloro or fluoro, PA1 c) C.sub.1-4 alkyl, PA1 d) halo-C.sub.1-4 alkyl, PA1 e) phenyl either unsubstituted or substituted with one or more of PA1 f) OR.sup.13 wherein R.sup.13 is PA1 1) methyl, PA1 2) hydroxy, PA1 3) C.sub.1-4 alkoxy, PA1 4) oxo or PA1 5) halo. PA1 0.04M Potassium phosphate, pH 7.0 PA1 0.05M KCl PA1 0.10M Sucrose PA1 0.03M EDTA PA1 0.01M Dithiothreitol PA1 3.5 mM NaCl PA1 1% Dimethylsulfoxide PA1 50-200 .mu.g Microsomal protein PA1 100 .mu.M .sup.14 C-[DL]HMG-CoA (0.05 .mu.Ci, 30-60 mCi/mmole) PA1 2.7 mM NADPH (nicotinamide adenine dinucleotide phosphate)
E is --CH.sub.2 CH.sub.2 --, --CH.dbd.CH--, or --(CH.sub.2).sub.3 --; and Z is ##STR12## wherein the dotted lines represent all of the possible oxidation states of the bicyclic system such as naphthalene, dihydro-, tetrahydro-, hexahydro-, octahydro-, and decahydronaphthalene;
X is --O-- or NR.sup.9 wherein
R.sup.9 is H or C.sub.1-3 alkyl;
R.sup.7 is C.sub.2-8 alkyl; and
R.sup.8 is H or --CH.sub.3 ; ##STR13##
wherein R.sup.10, R.sup.11 and R.sup.12 are independently
i) C.sub.1-4 alkyl, PA2 ii) C.sub.1-4 alkyl, PA2 iii) C.sub.2-8 alkanoyloxy, or PA2 iv) halo-C.sub.1-4 alkyl, PA2 v) halo, such as bromo, chloro or fluoro, PA2 i) hydrogen, PA2 ii) C.sub.1-8 alkanoyl, PA2 iii) benzoyl, PA2 iv) phenyl, PA2 v) halophenyl, PA2 vi) phenyl-C.sub.1-3 alkyl, either unsubstituted or substituted with one or more halogen, C.sub.1-4 alkoxy, C.sub.1-4 alkyl or halo-C.sub.1-4 alkyl, PA2 vii) C.sub.1-9 alkyl, PA2 viii) cinnamyl, PA2 ix) halo-C.sub.1-4 alkyl, PA2 x) allyl, PA2 xi) C.sub.3-6 cycloalkyl-C.sub.1-3 alkyl, PA2 xii) adamantyl-C.sub.1-3 alkyl, ##STR14## wherein n is 0-2, and is halo such as chloro, bromo or fluoro, or C.sub.1-4 alkyl, and ##STR15## wherein the dotted lines represent possible double bonds there being 0, 1 or 2 double bonds; m represents 1, 2 or 3; and
R.sup.15 is
In the discussion of the prior art at pages 2 and 3 of the above European patent, it is indicated that. HMG CoA reduotase inhibitors reported in the patent literature and elsewhere include compactin; mevinolin, di- and tetrahydro derivatives thereof; analogs with different esters in the 8-position of the polyhydronaphthalene moiety, totally synthetic analogs, wherein the polyhydronaphthalene moiety is replaced by substituted mono- and bicyclic aromatics. The applicant states at pages 3 and 4 as follows:
"But in all instances the active compound included a 4-hydroxytetrahydropyran-2-one ring or the corresponding 3,5-dihydroxy acid, or derivatives thereof, formed by opening the pyranone ring such as: ##STR16## In all of these compounds the 3,5-dihydroxy acid or corresponding lactone moiety is present and the particular stereochemistry depicted is essential for manifestation of the optimum enzyme inhibitory activity."
GB 1,586,152 discloses a group of synthetic compounds of the formula ##STR17## in which E represents a direct bond, a C.sub.1-3 alkylene bridge or a vinylene bridge and the various R's represent a variety of substituents.
The activity reported in the U.K. patent is less than 1% that of compactin.
U.S. Pat. No. 4,375,475 to Willard et al discloses hypocholesterolemic and hypolipemic compounds having the structure ##STR18## wherein A is H or methyl; E is a direct bond, --CH.sub.2 --, --CH.sub.2 --CH.sub.2 --, --CH.sub.2 --CH.sub.2 --CH.sub.2 -- or --CH.dbd.CH--; R.sub.1, R.sub.2 and R.sub.3 are each selected from H, halogen, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, phenyl, phenyl substituted by halogen, C.sub.1-4 alkoxy, C.sub.2-8 alkanoyloxy, C.sub.1-4 alkyl, or C.sub.1-4 haloalkyl, and OR.sub.4 in which R.sub.4 is H, C.sub.2-8 alkanoyl, benzoyl, phenyl, halophenyl, phenyl C.sub.1-3 alkyl, C.sub.1-9 alkyl, cinnamyl, C.sub.1-4 haloalkyl, allyl, cycloalkyl-C.sub.1-3 -alkyl, adamantyl-C.sub.1-3 -alkyl, or substituted phenyl C.sub.1-3 -alkyl in each of which the substituents are selected from halogen, C.sub.1-4 alkoxy, C.sub.1-4 alkyl, or C.sub.1-4 haloalkyl; and the corresponding dihydroxy acids resulting from the hydrolytic opening of the lactone ring, and the pharmaceutically acceptable salts of said acids, and the C.sub.1-3 alkyl and phenyl, dimethylamino or acetylamino substituted C.sub.1-3 alkyl esters of the dihydroxy acids; all of the compounds being the enantiomers having a 4 R configuration in the tetrahydropyran moiety of the trans racemate shown in the above formula.
GB 2162-179-A discloses naphthyl analogues of mevalolactone useful as cholesterol biosynthesis inhibitors having the structure ##STR19## wherein R.sub.1 .dbd.1-3C alkyl; Z is a gp. of formula Z.sub.1 or Z.sub.2 : ##STR20##
R.sub.7 .dbd.H, a hydrolysable ester gp. or a cation.
European Patent No. 164-698-A discloses preparation of lactones useful as anti-hypercholesterolemic agents by treating an amide with an organic sulphonyl halide R.sup.5 SO.sub.2 X, then removing the protecting group Pr. ##STR21## wherein
X=halo;
Pr=a carbinol-protecting group;
R.sup.1 =H or CH.sub.3 ;
R.sup.3, R.sup.4 =H, 1-3C alkyl or phenyl -(1-3C alkyl), the phenyl being optionally substituted by 1-3C alkyl, 1-3C alkoxy or halo;
R.sup.2 =a group of formula (A) or (B): ##STR22##
R.sup.6 =H or OH;
R=H or CH.sub.3 ;
a, b, c and d=optional double bonds;
R.sup.7 =phenyl or benzyloxy, the ring in each case being optionally substituted by 1-3C alkyl or halo;
R.sup.8, R.sup.9 =1-3C alkyl or halo;
R.sup.5 =1-3C alkyl, phenyl or mono- or di-(1-3C alkyl)phenyl.
Anderson, Paul Leroy, Ger. Offen. DE 3,525,256 discloses naphthyl analogs of mevalonolactones of the structure ##STR23## wherein R.sup.1 is alkyl, Z=Q, Q.sup.1 ; R.sup.7 =or a hydrolyzable ester group useful as inhibitors of cholesterol biosynthesis and in treatment of atherosclerosis.
WO 8402-903 (based on U.S. application Ser. No. 460,600, filed Jan. 24, 1983) filed in the name of Sandoz AG discloses mevalono-lactone analogues useful as hypolipoproteinaemic agents having the structure ##STR24## wherein the two groups Ro together form a radical of formula ##STR25##
wherein R.sub.2 is hydrogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, (except t-butoxy), trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy,
R.sub.3 is hydrogen, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, with the provisos that not more than one of R.sub.2 and R.sub.3 is trifluoromethyl, not more than one of R.sub.2 and R.sub.3 is phenoxy, and not more than one of R.sub.2 and R.sub.3 is benzyloxy,
R.sub.1 is hydrogen, C.sub.1-6 alkyl, fluoro, chloro or benzyloxy,
R.sub.4 is hydrogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, (except t-butoxy), trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy,
R.sub.5 is hydrogen, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy,
R.sub.5a is hydrogen, C.sub.1-2 alkyl, C.sub.1-2 alkoxy, fluoro or chloro, and with the provisos that not more than one of R.sub.4 and R.sub.5 is trifluoromethyl, not more than one of R.sub.4 and R.sub.5 is phenoxy and not more than one of R.sub.4 and R.sub.5 is benzyloxy, ##STR26## wherein n is 0, 1, 2 or 3 and both q's are 0 or one is 0 and the other is 1, ##STR27## wherein R.sub.6 is hydrogen or C.sub.1-3 alkyl, with the general proviso that --X--Z and the R.sub.4 bearing phenyl group are ortho to each other;
in free acid form or in the form of a physiologically-hydrolysable and acceptable ester or a .delta. lactone thereof or in salt form.
WO 8603-488-A (Sandoz AG) discloses indene analogues of mevalolactone, useful as hypolipoproteinaemia and anti-atherosclerotic agents, in free acid form or in the form of an ester or delta-lactone or in salt form which have the formula ##STR28##
R.dbd.H or primary or secondary 1-6C alkyl;
R.sub.1 .dbd.primary or secondary 1-6C alkyl;
or R+R.sub.1 .dbd.(CH.sub.2).sub.m or (Z)--CH.sub.2 --CH.dbd.CH--CH.sub.2 ;
m.dbd.2-6;
R.sub.o .dbd.1-6C alkyl, 3-7C cycloalkyl or R.sub.4, R.sub.5, R.sub.6 -substituted phenyl;
R.sub.2, R.sub.4 .dbd.H, 1-4C alkyl, 1-4C alkoxy (except t-butoxy), CF.sub.3, F, Cl, phenoxy or benzyloxy;
R.sub.3 and R.sub.5 .dbd.H, 1-3C alkyl, 1-3C alkoxy, CF.sub.3, F, Cl, phenoxy or benzyloxy;
R.sub.6 .dbd.H, 1-2C alkyl, 1-2C alkoxy, F or Cl;
provided that there may only be one each of CF.sub.3, phenoxy or benzyloxy on each of the phenyl and indene rings;
X.dbd.(CH.sub.2).sub.n or --(C.sub.2).sub.q --CH.dbd.CH(CH.sub.2).sub.q --;
n.dbd.1-3;
both q's.dbd.0, or one is 0 and the other is 1;
Z.dbd.--Q--CH.sub.2 --C(R.sub.10)(OH)--CH.sub.2 COOH, in free acid form or in the form of an ester or delta-lactone or salt;
Q.dbd.CO, --C(OR.sub.7).sub.2 -- or CHOH;
R'.sub.7s .dbd.the same primary or secondary 1-6C alkyl, or together are (CH.sub.2).sub.2 or (CH.sub.2).sub.3 ;
R.sub.10 .dbd.H or 1-3C alkyl;
provided that Q may be other than CHOH only when X is CH.dbd.CH or CH.sub.2 --CH.dbd.CH and/or R.sub.10 is 1-3C alkyl.
Heathcock, J. Med. Chem., 1989, 32, 197 discloses the synthesis of a monocyclic compound of the structure ##STR29## However, this compound is relatively inactive as an HMG CoA reductase inhibitor.